Imaging, Pulmonary Function, and Histopathologic Findings of Persistent Fibrosis in a Longitudinal Cohort 3 Years after COVID-19

Abstract

Rationale: Survivors of severe coronavirus disease (COVID-19) frequently have persistent radiologic abnormalities beyond one year. Scant data exist for long-term outcomes of COVID-19. Objectives: To characterize a longitudinal multiethnic cohort of COVID-19 survivors 3 years after infection; to identify clinical factors associated with post-COVID-19 fibrotic-like abnormalities; to describe changes in radiologic abnormalities at 4 months, 15 months, and 3 years; and to describe histopathologic features of lung parenchyma from participants with fibrotic-like abnormalities at 3 years. Methods: One hundred two survivors of severe or critical COVID-19 (50% mechanically ventilated, all requiring oxygen supplementation) from a single-center, prospective, longitudinal, multiethnic cohort completed inspiratory and expiratory high-resolution chest imaging, pulmonary function testing, and physical performance testing 3 years after hospitalization. More than 70% participated in earlier follow up visits at 4 and/or 15 months. Factors associated with persistent fibrotic-like abnormalities were examined using multivariable logistic regression with covariate-balanced propensity scores to estimate adjusted associations. For subjects with more than one imaging study, changes in ground-glass opacities, reticulations, and traction bronchiectasis were semiquantitatively analyzed and qualitatively assessed. Five participants with post-COVID-19 fibrosis scores in the top quartile underwent transbronchial biopsy for histopathologic analysis. Results: Fibrotic-like abnormalities, including reticulations and traction bronchiectasis, were present in 61% of survivors of severe or critical COVID-19. In adjusted analyses, fibrotic-like abnormalities were positively associated with male sex, lower body mass index (BMI), shorter leukocyte telomere length, increased severity of illness and mechanical ventilation; they were negatively associated with Black race. Participants with fibrotic-like abnormalities were more likely to have reduced diffusion capacity and reduced 6-minute-walk distance. Reticulations, as assessed by semiquantitative analysis, modestly improved across all time points, even between 15 months and 3 years. Qualitatively, most participants had stable fibrotic-like abnormalities across all time points, with 9% improving from 15 months to 3 years and none worsening. Lung parenchyma from transbronchial biopsies of five individuals with elevated fibrotic scores showed small airway histopathology, consistent with air trapping during expiration, and infrequent interstitial thickening and fibrosis. Conclusions: Despite modest improvements in radiologic fibrotic-like abnormalities 3 years after hospitalization, their continued presence and their association with reduced diffusion capacity and reduced walk distance highlight the long-term consequences of severe COVID-19, which may require further monitoring.

Keywords: air trapping; lung histopathology; post–COVID-19 fibrosis; pulmonary function; telomeres.